Although a wealth of evidence suggests an interaction between the opioid and immune systems, very few studies have investigated the role of behavioral and environmental variables in this interaction. One variable of particular importance in understanding long-term opioid use and relapse relates to the ease with which many of the effects of opioid administration and withdrawal can be conditioned to stimuli in the environment. Accordingly, it is likely that the alterations in immune function which occur as the result of acute as well as long-term opioid administration might also become conditioned and therefore have the potential to persist long after opioid use has been terminated. Thus, it is our objective to examine opioid-induced alterations in immune function with emphasis on the role of behavioral, environmental, and pharmacological variables in these interactions. Our first specific aim provides background information for these investigations by exploring the unconditioned effects of acute and chronic opioid administration. These investigations include a range of doses of the opioid agonist morphine, given either acutely (one daily dose) or chronically (one daily dose for 1,3,5 or more days). Immune function will be assessed with several different rodent in vitro assays, including mitogen-stimulation of splenic, lymph node and whole-blood lymphocytes, a natural-killer cell assay, assessment of interleukin-1, interleukin-2 and interferon production and flow cytometry analysis to assess alterations in leukocyte subpopulations. Additional in vivo measures of antibody production will also be employed. Our second specific aim examines the role of conditioning in opioid-induced alterations in immune function. Given previous demonstrations that stimuli paired with opioid administration can elicit many of the signs and symptoms of opioid administration as well as modulate the development of tolerance to opioid effects, we will determine whether stimuli associated with morphine will induce morphine-like alterations in immune function (in the absence of morphine) and also whether stimuli associated with morphine administration will modulate the effects morphine has on immune function. The retention and extinction of these conditioned alterations in immune function will also be examined. Our third specific aim investigates the mechanisms which underlie interactions between morphine-induced alterations in immune function and behavioral/environmental events. These studies will employ selective antagonists to examine the role of opioid and catecholaminergic systems in opioid-induced alterations in immune function. In all studies, pharmacological variables such as dose of morphine, and duration of morphine administration will be assessed as well as behavioral/environmental variables such as the nature of the conditioning environment, the number of conditioning trials and preexposure to the conditioning stimuli.